“Vinylogs” and “Acetylenylogs” of β-Adrenergic Agents

Vinylogous (Groups III and V ) and acetylenologous (Group IV ) analogs of the classical β-adrenergic agents — stimulants and blockers — were prepared in order to evaluate the effect of degree of saturation, position of unsaturation and rigidity of the chain linking the aromatic ring and the amino containing functional group on biological activity. Derivatives from Group III , which represent 4-aryl-3-butenyl-2-ol-amine analogs of Group II , retained β₁-adrenoceptor antagonist activity albeit substantially less potent (50–200-fold) than that possessed by their aryloxy counterparts. Consistent with the SAR for Group II compounds, substitution at position 2 of the aromatic ring yielded the most potent antagonists ( 5a, 5d, 5g ), with K_B's ranging from 73–93 nM while 3,4-dichloro substitution ( 5e ) markedly reduced antagonist potency (K_B = 2,400 nM). Agonist activity was also noted for 5b and 5d , suggesting that these compounds may be best classified as partial agonists. Representatives from Groups IV and V were inactive as antagonists at the β₁-adrenoceptor confirming the importance of the spatial relationship between the hydroxyl and the amino nitrogen.     

Serotonin-induced increase in cAMP in ganglia isolated from the myenteric plexus of the guinea pig small intestine: Mediation by a novel 5-HT receptor

Serotonin (5-HT) is a mediator (through 5-HT_1P receptors) of slow EPSPs in myenteric ganglia of the small intestine. The effect of 5-HT can be mimicked by elevating cAMP; therefore, we tested the hypothesis that the slow EPSP-like response to 5-HT is cAMP-mediated. Guinea pig gut was enzymatically dissociated; myenteric ganglia remained intact and were collected by filtration. Neurons in the isolated ganglia retained their ability to manifest the slow EPSP-like response to 5-HT. Exposure to 5-HT raised the ganglionic level of cAMP (ED₅₀ 0.3 μM). This effect was not antagonized by the 5-HT_1P antagonist, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (100.0 μM), or mimicked by the 5-HT_1P agonist, 5-hydroxyindalpine (10.0 μM). Increases in cAMP were also evoked by the 5-HT₁ agonist, 5-carboxyamidotryptamine (10.0 μM), the 5-HT₂ agonist, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 1.0–10.0 μM), and by the 5-HT₄ agonists, renzapride (1.0–10.0 μM) and 5-methoxytryptamine (1.0–10.0 μM); however, neither the 5-HT₁/5-HT₂ antagonists, spiperone, methysergide, and methiothepin, nor the 5-HT₄ antagonist, tropisetron (ICS 205–930; 10.0 μM), were able to inhibit the rise in cAMP evoked by these compounds or by 5-HT (0.1–10.0 μM). The 5-HT-evoked elevation of cAMP was antagonized by ketanserin (10.0 μM), which also blocked the effects of 5-methoxytryptamine and DOI, but not those of renzapride. The effective concentration of DOI, however, was higher than that needed for activation of 5-HT₂ receptors, and Northern analysis using a cDNA probe encoding the rat 5-HT₂ receptor failed to reveal the presence of 5-HT₂ mRNA in myenteric ganglia, although it hybridizes with mRNA of the right size in the guinea pig brain. Compounds that failed to change levels of cAMP or to antagonize the action of 5-HT included 8-hydroxy-di-n-propylamino tetralin, R58639, R88226, and sumatriptan. It is concluded that the receptor responsible for the 5-HT-induced rise in cAMP in ganglia isolated from the guinea pig myenteric plexus is not a known subtype of 5-HT receptor. Since the pharmacology of this novel receptor is different from that of the slow EPSP-like response to 5-HT, the receptor probably does not mediate the slow EPSP. © 1993 Wiley-Liss, Inc.     

Vertical interpositional augmentation genioplasty with porous polyethylene

Recent advances in the field of biomatrix porous implant technology has stirred the interest of the oral and maxillofacial surgical community. One such material (Medpor), is a biocompatible, large-pore, high-density polyethylene implant which has proven both experimentally and clinically to fulfil the criterion for maxillofacial reconstructive and aesthetic surgical grafting.     

Pediatric intracranial pressure monitoring in hypoxic and nonhypoxic brain injury

We reviewed the results of all pediatric patients undergoing intracranial pressure (ICP) monitoring in a 2-year period at our institution. The outcome of patients suffering hypoxia or ischemic injuries (HII) is compared to those suffering non-hypoxic or non-ischemic injuries (NHII). Thirty-four patients had ICP monitors placed during the study period. Inconplete patient information led to the exclusion of 5 patients. An additional 5 patients were excluded because no measures to control ICP were taken after the monitor was placed. Twenty-four patients required treatment for raised ICP (hyperventilation, 24; mannitol, 19; barbiturate coma, 6). Admission Glasgow Coma Score in patients suffering HII (median score 5) and NHII (median score 6) were not significantly different (Mann-Whitney U Test). Only 2 of 8 patients with HII were near-drowning vietims. The remaining 6 had HII from other causes (5 survivors of various forms of asphyxia and 1 of cardiac arrest). All 8 patients had poor outcomes (1 severely disabled; 7 died). The 16 patients with NHII had a variety of diagnoses (6 trauma, 5 encephalitis, 4 bacterial meningitis, 1 diabetic ketoacidosis). Among these, 6 had good outcomes and 10 poor outcomes (2 severely disabled, 2 vegetative, and 6 died). The difference in outcome between patients with NHII and HII is significant at P=0.059 (Fischer Exact test). Patients with NHII may benefit from ICP monitoring. Patients with HII from near-drowning and other causes did not appear to benefit from ICP monitoring and interventions directed at controlling ICP.